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Summary The plasma membrane (PM) is composed of a complex lipid mixture that forms heterogeneous membrane environments. Yet, how small-scale lipid organization controls physiological events at the PM remains largely unknown. Here, we show that ORP-related Osh lipid exchange proteins are critical for the synthesis of phosphatidylinositol (4,5)-bisphosphate [PI(4,5)P2], a key regulator of dynamic events at the PM. In real-time assays, we find that unsaturated phosphatidylserine (PS) and sterols, both Osh protein ligands, synergistically stimulate phosphatidylinositol 4-phosphate 5-kinase (PIP5K) activity. Biophysical FRET analyses suggest an unconventional co-distribution of unsaturated PS and phosphatidylinositol 4-phosphate (PI4P) species in sterol-containing membrane bilayers. Moreover, using in vivo imaging approaches and molecular dynamics simulations, we show that Osh protein-mediated unsaturated PI4P and PS membrane lipid organization is sensed by the PIP5K specificity loop. Thus, ORP family members create a nanoscale membrane lipid environment that drives PIP5K activity and PI(4,5)P2 synthesis that ultimately controls global PM organization and dynamics., Graphical Abstract, Highlights • The Osh lipid exchange proteins are required to maintain PI(4,5)P2 levels in the PM • Unsaturated PS and sterols synergistically stimulate PIP5K activity • The specificity loop conserved in PIP5Ks serves as a lipid sensor • A simulation model of the PIP5K specificity loop embedded in a lipid bilayer, Nishimura et al. show that the Osh lipid exchange proteins are required for PI(4,5)P2 synthesis, a key regulator of global plasma membrane organization and function. The Osh proteins form a unique membrane lipid environment with unsaturated phosphatidylserine and sterols that specifies PIP 5-kinase activity at the plasma membrane.

Objective Shotgun lipidomics enables an extensive analysis of lipids from tissues and fluids. Each specimen requires appropriate extraction and processing procedures to ensure good coverage and reproducible quantification of the lipidome. Adipose tissue (AT) has become a research focus with regard to its involvement in obesity-related pathologies. However, the quantification of the AT lipidome is particularly challenging due to the predominance of triacylglycerides, which elicit high ion suppression of the remaining lipid classes. Methods We present a new and validated method for shotgun lipidomics of AT, which tailors the lipid extraction procedure to the target specimen and features high reproducibility with a linear dynamic range of at least 4 orders of magnitude for all lipid classes. Results Utilizing this method, we observed tissue-specific and diet-related differences in three AT types (brown, gonadal, inguinal subcutaneous) from lean and obese mice. Brown AT exhibited a distinct lipidomic profile with the greatest lipid class diversity and responded to high-fat diet by altering its lipid composition, which shifted towards that of white AT. Moreover, diet-induced obesity promoted an overall remodeling of the lipidome, where all three AT types featured a significant increase in longer and more unsaturated triacylglyceride and phospholipid species. Conclusions The here presented method facilitates reproducible systematic lipidomic profiling of AT and could be integrated with further –omics approaches used in (pre-) clinical research, in order to advance the understanding of the molecular metabolic dynamics involved in the pathogenesis of obesity-associated disorders., Graphical abstract Image 1, Highlights • Validated shotgun lipidomics method of AT covering 300 lipids of 20 classes and linear dynamic range of 4 orders of magnitude. • Increase of longer and more unsaturated triacylglycerides and phospholipids in brown and white AT under high-fat diet. • Differences in the lipidomes of gonadal, subcutaneous and brown AT.

We thank the nursing staff at the Hospital Santa Cruz, in particular Edite Tomas Mateus and Manuel Belo Costa for their enthusiastic involvement in this project and help in blood collection. This work was supported by iNOVA4Health - UID/Multi/04462/2013, a program financially supported by FCT (Foundation for Science and Technology of the Portuguese Ministry of Science and Higher Education) through national funds and co-funded by FEDER under the PT2020 Partnership, and Programas de Atividades Conjuntas (PAC) (Ref. No 03/SAICT/2015). ND is a holder of PhD fellowship from the FCT (Ref. No: SFRH/BD/51877/2012). Shotgun lipidomic analysis of 203 lipids in 13 lipid classes performed on blood plasma of donors who had just suffered an acute coronary syndrome (ACS, n = 74), or an ischemic stroke (IS, n = 21), or who suffer from stable angina pectoris (SAP, n = 78), and an age-matched control cohort (n = 52), showed some of the highest inter-lipid class correlations between cholesteryl esters (CE) and phosphatidylcholines (PC) sharing a common fatty acid. The concentration of lysophospatidylcholine (LPC) and ratios of concentrations of CE to free cholesterol (Chol) were also lower in the CVD cohorts than in the control cohort, indicating a deficient conversion of Chol to CE in the blood plasma in the CVD subjects. A non-equilibrium reaction quotient, Q′, describing the global homeostasis of cholesterol as manifested in the blood plasma was shown to have a value in the CVD cohorts (Q′ACS = 0.217 ± 0.084; Q′IS = 0.201 ± 0.084; Q′SAP = 0.220 ± 0.071) that was about one third less than in the control cohort (Q′Control = 0.320 ± 0.095, p < 1 × 10−4), suggesting its potential use as a rapid predictive/diagnostic measure of CVD-related irregularities in cholesterol homeostasis. publishersversion published

Degradable bone substitutes like Mg-based alloys are promising due to their good osseointegration and biocompatibility. The objective of this study was to investigate the influence of additional coatings on the degradation behavior, osseointegration and gas release of 128 open porous scaffolds (O 4 mm, length 5 mm) of the magnesium alloy LAE442 (4 wt% Li, 4 wt% Al, 2 wt% rare earths). Along a base layer of MgF2 polylactide acid (PLA) or calcium phosphate (CaP) were applied. While the resorbable PLA was supposed to delay the magnesium degradation, the CaP should form a nutrient depot for growing bone. The control group consisted of 32 β-tricalcium phosphate (TCP) scaffolds. The scaffolds were inserted into the greater trochanter of 80 adult female ZiKa rabbits. X-ray and in vivo μCT scans were performed postoperatively at regular intervals of 6, 12, 24, 36 weeks. Gas accumulation, scaffold degradation and osseointegration were evaluated. In comparison, PLA-coated scaffolds degraded slightly slower, but had a significantly greater amount of gas in the medullary canal at weeks 2 and 4 compared to CaP-coated scaffolds. CaP-coated scaffolds showed better values for drill hole closure and a significantly higher number of bone-scaffold contacts from week 12 to 36 compared to PLA. Furthermore, CaP-coated scaffolds showed higher bone volume and more new formed bone trabeculae than PLA-coated scaffolds. In total, an additional coating with CaP seemed to be promising in improving the degradation resistance and osseointegration, when using biodegradable bone substitutes.

// Maria L. Torgersen 1 , Tove Irene Klokk 1 , Simona Kavaliauskiene 1, 2 , Christian Klose 3 , Kai Simons 3 , Tore Skotland 1 , Kirsten Sandvig 1, 2 1 Department of Molecular Cell Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Norway, and Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Norway 2 Department of Molecular Biosciences, University of Oslo, Norway 3 Lipotype GmbH, Dresden, Germany Correspondence to: Maria L. Torgersen, email: marialy@rr-research.no Keywords: hydroxyoleic acid, minerval, membrane lipid therapy, EGFR, ricin Received: June 20, 2016 Accepted: October 17, 2016 Published: November 22, 2016 ABSTRACT 2-hydroxyoleic acid (OHOA, Minerval ® ) is an example of a substance used for membrane lipid therapy, where the cellular membranes rather than specific proteins constitute the therapeutical target. OHOA is thought to mediate its anti-tumor effect by affecting the biophysical properties of membranes, which leads to altered recruitment and activation of amphitropic proteins, altered cellular signaling, and eventual cell death. Little is known about the initial signaling events upon treatment with OHOA, and whether the altered membrane properties would have any impact on the dynamic intracellular transport system. In the present study we demonstrate that treatment with OHOA led to a rapid release of intracellular calcium and activation of multiple signaling pathways in HeLa cells, including the PI3K-AKT1-MTOR pathway and several MAP kinases, in a process independent of the EGFR. By lipidomics we confirmed that OHOA was incorporated into several lipid classes. Concomitantly, OHOA potently increased retrograde transport of the plant toxin ricin from endosomes to the Golgi and further to the endoplasmic reticulum. The OHOA-stimulated ricin transport seemed to require several amphitropic proteins, including Src, phospholipase C, protein kinase C, and also Ca 2+ /calmodulin. Interestingly, OHOA induced a slight increase in endosomal localization of the retromer component VPS35. Thus, our data show that addition of a lipid known to alter membrane properties not only affects signaling, but also intracellular transport.

The formability of deep drawing can be extended by combining it with a subsequent high-speed forming method such as electromagnetic forming. However, up to now, no sufficient systematic understanding of the underlying principles or of a successful design of such coupled processes has been gained. Hence, in this work, a methodology for the analysis and design of such process chains is presented. This approach comprises a new method for the experimentally based determination of quasi-static and high-speed forming limits along close to proportional strain paths, a constitutive visco-plastic, anisotropic material model with a rate dependent ductile damage formulation, which allows for the accurate numerical prediction of forming limits for complicated forming operations under a largely varying strain rate, and finally the actual application of both to a combined quasi-static and high-speed forming operation. In doing so, material areas are identified that are deep drawn up to a degree immediately before necking occurs and then electromagnetically be formed beyond the quasi-static forming limit without damage. This proves that an extension of formability is here achieved due to a change in strain rate rather than in the strain path.

Acute metabolic changes in plasma membrane (PM) lipids, such as those mediating signalling reactions, are rapidly compensated by homeostatic responses whose molecular basis is poorly understood. Here we show that the extended synaptotagmins (E-Syts), endoplasmic reticulum (ER) proteins that function as PtdIns(4,5)P2- and Ca2+-regulated tethers to the PM, participate in these responses. E-Syts transfer glycerolipids between bilayers in vitro, and this transfer requires Ca2+ and their lipid-harbouring SMP domain. Genome-edited cells lacking E-Syts do not exhibit abnormalities in the major glycerolipids at rest, but exhibit enhanced and sustained accumulation of PM diacylglycerol following PtdIns(4,5)P2 hydrolysis by PLC activation, which can be rescued by expression of E-Syt1, but not by mutant E-Syt1 lacking the SMP domain. The formation of E-Syt-dependent ER–PM tethers in response to stimuli that cleave PtdIns(4,5)P2 and elevate Ca2+ may help reverse accumulation of diacylglycerol in the PM by transferring it to the ER for metabolic recycling. Accepted version

Im Fokus dieses Fachbeitrags steht die im Rahmen des Sonderforschungsbereichs 1153 angestrebte Entwicklung einer Prozesskette zur Fertigung einer hybriden Lagerbuchse aus Aluminium und Stahl. Es werden die Werkzeugkonzepte zur Halbzeugherstellung durch das Verbundstrangpressen sowie zum anschließenden Gesenkschmieden der hybriden Lagerbuchse vorgestellt. Des Weiteren wird ein Ausblick auf die numerische Prozessauslegung gegeben und erste Ergebnisse möglicher Erwärmungsstrategien werden präsentiert. The focus of this paper is on the process chain development that is being researched within the Collaborative Research Centre 1153 for the production of a hybrid bearing bushing made of aluminium and steel. Here, the tool concepts for the production of semi-finished products through compound extrusion and the subsequent forging to a hybrid bearing bushing are introduced. Furthermore, an outlook on the numerical process design and the first results of the possible heating strategies are given.

Sheet metal forming is an inherent part of todays production industry. A major goal is to increase the forming limits of classical deep-drawing processes. One possibility to achieve that is to combine the conventional quasi-static (QS) forming process with electromagnetic high-speed (HS) post-forming. This work focuses on the finite element analysis of such combined forming processes to demonstrate the improvement which can be achieved. For this purpose, a cooperation of different institutions representing different work fields has been established. The material characterization is based on flow curves and forming limit curves for low and high strain rates obtained by novel testing devices. Further experimental investigations have been performed on the process chain of a cross shaped cup, referring to both purely quasi-static and quasi-static combined with electromagnetic forming. While efficient mathematical optimization algorithms support the new viscoplastic ductile damage modelling to find the optimum parameters based on the results of experimental material characterization, the full process chain is studied by means of an electro-magneto-mechanical finite element analysis. The constitutive equations of the material model are integrated in an explicit manner and implemented as a user material subroutine into the commercial finite element package LS-DYNA.

Gene and protein expression data provide useful resources for understanding brain function, but little is known about the lipid composition of the brain. Here, we perform quantitative shotgun lipidomics, which enables a cell-type-resolved assessment of the mouse brain lipid composition. We quantify around 700 lipid species and evaluate lipid features including fatty acyl chain length, hydroxylation, and number of acyl chain double bonds, thereby identifying cell-type- and brain-region-specific lipid profiles in adult mice, as well as in aged mice, in apolipoprotein-E-deficient mice, in a model of Alzheimer's disease, and in mice fed different diets. We also integrate lipid with protein expression profiles to predict lipid pathways enriched in specific cell types, such as fatty acid beta-oxidation in astrocytes and sphingolipid metabolism in microglia. This resource complements existing brain atlases of gene and protein expression and may be useful for understanding the role of lipids in brain function. Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.

AimGenetic investigation of human plasma lipidome to get insights into lipid-related disorders beyond traditional lipid measures.Methods and ResultsWe performed a genome-wide association study (GWAS) of 141 lipid species (n=2,181 individuals), followed by phenome-wide scans (PheWAS) with 44 clinical endpoints related to cardiometabolic, psychiatric and gastrointestinal disorders (n=456,941 individuals). SNP-based heritability for lipid species ranged from 0.10-0.54. Lipids with long-chain polyunsaturated fatty acids showed higher heritability and genetic sharing, suggesting considerable genetic regulation at acyl chains levels. We identified 35 genomic regions associated with at least one lipid species (P−8), revealing 37 new SNP-lipid species pair associations e.g. new association between ABCG5/8 and CE(20:2;0). PheWAS of lipid-species-associated loci suggested new associations of BLK with obesity, FADS2 with thrombophlebitis, and BLK and SPTLC3 with gallbladder disease (false discovery rate SYNGR1, MIR100HG, and PTPRN2 in desaturation and/or elongation of fatty acids. At known lipid loci (FADS2, APOA5 and LPL), genetic associations provided detailed insights to their roles in lipid biology and diseases. We also show that traditional lipid measures may fail to capture lipids such as lysophospatidylcholines (LPCs) and phosphatidylcholines (PCs) that are potential disease risk factors, but are not included in routine screens. The full genome-wide association statistics are available on the web-based database (http://35.205.141.92).ConclusionOur study reveals genetic regulation of plasma lipidome and highlights the potential of lipidomic profiling in disease gene mapping.

The use of lightweight materials is one possibility to limit the weight of vehicles and to reduce CO2 emissions. However, the mechanical properties and weight-saving potential of mono-materials are limited. Material compounds can overcome this challenge by combining the advantages of different materials in one component. Lateral angular co-extrusion (LACE) allows the production of coaxial semi-finished products consisting of aluminum and steel. In this study, a finite element model of the LACE process was built up and validated by experimental investigations. A high degree of agreement between the calculated and experimentally determined forces, temperatures, and the geometrical shape of the hybrid profiles was achieved. In order to determine suitable parameters for further extrusion experiments, the influence of different process parameters on material flow and extrusion force was investigated in a numerical parametric study. Both the temperature and extrusion ratio showed a significant influence on the occurring maximum extrusion force as well as the material flow inside the LACE tool. The maximum force of 2.5 MN of the employed extrusion press was not exceeded. An uneven material flow was observed in the welding chamber, leading to an asymmetric position of the steel rod in the aluminum matrix.

Porous magnesium implants have been investigated for some time for their orthopaedic applicability as resorbable bone substitutes. The objective of this study was to evaluate the in vivo degradation behaviour and osseointegration of open-pored scaffolds made of the two magnesium alloys, LAE442 (n = 40) and Mg-La2 (n = 40). Cylindrical magnesium scaffolds (diameter 4 mm, length 5 mm) with defined interconnecting pore structure were produced by investment casting and coated with MgF2. Commercially available porous s-tricalcium phosphate scaffolds (TCP, n = 40) of the same dimensions served as control. The scaffolds were inserted in the cancellous part of the greater trochanter of both femurs in rabbits and evaluated over a period of 36 weeks using regular clinical, radiological and in vivo µCT examinations. No clinical adverse reactions were observed in any of the scaffolds. The X-ray and µCT image evaluation of La2 showed fast and inhomogeneous degradation behaviour with increased gas formation and a rapid loss of scaffold structure and shape from week 12 on. In comparison, the LAE442 scaffolds showed a slow, homogeneous degradation with low but continuous gas production over the entire study period. Furthermore, LAE442 scaffolds showed comparatively better osseointegration with more trabecular contacts than La2 scaffolds and retained their original scaffold structure. Although the TCP control group demonstrated the best osseointegration, it showed overly-rapid degradation. Based on the results of this study, the LAE422 scaffolds have promising properties for further investigations in weight-bearing bone defects.

Aims: To characterize and compare coronary artery disease (CAD) risk and detailed lipidomic profiles of individuals with familial and population-ascertained hyperlipidemias.Methods and Results: We determined incident CAD risk for 760 members of 66 hyperlipidemic families (≥ 2 first degree relatives with the same hyperlipidemia) and 19,644 Finnish FINRISK population study participants. We also quantified 151 lipid species in plasma or serum samples from 550 members of 73 hyperlipidemic pedigrees and 897 FINRISK participants using a mass spectrometric shotgun lipidomics platform. Hyperlipidemias (LDL-C or triacylglycerides over 90th population percentile) were associated with increased CAD risk (high LDL-C: HR 1.74, 95% CI 1.48–2.04; high triacylglycerides: HR 1.38, 95% CI 1.09–1.74) and the risk estimates were very similar between the family and population samples. High LDL-C was associated with altered levels of 105 lipid species in families (p-value range 0.033–7.3*10−20 at 5% false discovery rate) and 51 species in the population samples (p-value range 0.017–6.8*10−21). Hypertriglyceridemia was associated with altered levels of 117 lipid species in families (p-value range 0.035–1.8*10−49) and 119 species in the population sample (p-value range 0.038–2.3*10−56). The lipidomics profiles of hyperlipidemias were highly similar in families and population samples.Conclusion: We identified distinct lipidomic profiles associated with high LDL-C and triacylglyceride levels. CAD risk, lipidomic profiles and genetic profiles are highly similar between familial and population-ascertained hyperlipidemias, providing evidence of similar and overlapping underlying mechanisms. Our results do not support different screening and treatment for such hyperlipidemias.

In order to save weight and costs, different materials can be combined within one component. In the novel process chain being developed within the Collaborative Research Centre (CRC) 1153, joined semi-finished workpieces are used to produce hybrid solid components with locally adapted properties. Different materials are joined in an initial step before the forming process takes place. Hereby, the quality of the joining zone is improved by means of the thermo-mechanical treatment during the forming and machining processes. The lateral angular co-extrusion (LACE) approach is used to produce semi-finished workpieces because it allows for the production of coaxial semi-finished products consisting of aluminium and steel. In the further process chain, these semi-finished products are processed into hybrid bearing bushings with locally adapted properties by die forging. In the scope of this work, numerical investigations of the co-extrusion of aluminium-steel compounds were carried out using finite element (FE) simulation in order to examine the influence of the process parameters on the co-extrusion process. For this purpose, the relevant material properties of the aluminium alloy EN AW-6082 were determined experimentally and subsequently implemented in the numerical model. The obtained numerical model was used to study the impact of different ram speeds, press ratios and billet temperatures on the resulting extrusion forces and the material flow. The numerical results have been validated using force-time curves obtained from experimental extrusion tests carried out on a 2.5 MN laboratory extrusion press.

The size of all cells, from bacteria to vertebrates, is proportional to the growth rate set by nutrient availability, but the underlying mechanisms are unknown. Here, we show that nutrients modulate cell size andgrowth rate via the TORC2 signaling network in budding yeast. An important function of the TORC2 network is to modulate synthesis of ceramide lipids, which play roles in signaling. TORC2-dependent control of ceramide signaling strongly influences both cell size and growth rate. Thus, cells that cannot make ceramides fail to modulate their growth rate or size in response to changes in nutrients. PP2A associated with the Rts1 regulatory subunit (PP2ARts1) is embedded in a feedback loop that controls TORC2 signaling and helps set the level of TORC2 signaling to match nutrient availability. Together, the data suggest a model in which growth rate and cell size are mechanistically linked by ceramide-dependent signals arising from the TORC2 network.

Large bone defects or fractures must be treated with an implant or transplant. Resorbable implants are attractive as these require only one surgery, whereas bone autografts, which can be cut off from the same person's hip, require more than one procedure. Moreover, porous structures promote the ingrowth of the patient's bone. Thus, the objective of the present study was to develop open-pored biodegradable implant structures with different pore sizes that provide for both adequate degradation behaviour and mechanical properties that match with those of bone. The magnesium alloys LAE442 and La2 were employed in this study, as these materials are known to feature good biocompatibility and mechanical properties close to bone. It was possible to cast magnesium sponges with different pore sizes using the alloy LAE442. However, with the Mg La2 alloy, only sponges with a minimum pore size of 0.5 mm could be produced. Overall, the sponges cast with the LAE442 alloy showed higher strength, even though the strengths of the dense parts were similar in both alloys tested. In terms of castability and mechanical behaviour, the LAE442 alloy turned out to be more favourable. In order to adapt the implant degradation behaviour to the bone ingrowth behaviour, coating of the magnesium sponges with calcium phosphate and polylactic acid was also investigated. Additionally, the different coatings were tested on their adhesive forces and influences to the in-vitro degradation behaviour.

The present study focuses on the influence of longitudinal and charge weld seams on the possibility for their non-destructive testing in extruded profiles. For this, aluminum and magnesium alloys were extruded at different extrusion conditions using porthole dies and prepared for non-destructive testing. First, the electrical conductivity of profiles containing charge welds was measured on two measuring paths over the length of the profile and correlated to the respective mechanical properties and microstructures. Second, detailed measurements on specimens taken from similar profiles were done in order to evaluate and compare the detectability of longitudinal weld seams for different alloys.

Shotgun lipidomics is the comprehensive and quantitative analysis of the lipid composition of biological and clinical samples. Here we describe the application and performance of the Lipotype shotgun lipidomics technology in clinical high throughput screening projects for the identification of disease-specific lipid patterns as well as in organ-wide analysis aiming at the systemic understanding of lipid-related physiological processes.

Author(s): Cornish-Bowden, Athel; Cornish-Bowden, Athel; Rasnick, David; Heng, Henry H; Horne, Steven; Abdallah, Batoul; Liu, Guo; Ye, Christine J; Bloomfield, Mathew; Vincent, Mark D; Aldaz, C Marcelo; Karlsson, Jenny; Valind, Anders; Jansson, Caroline; Gisselsson, David; Graves, Jennifer A Marshall; Stepanenko, Aleksei A; Andreieva, Svitlana V; Korets, Kateryna V; Mykytenko, Dmytro O; Huleyuk, Nataliya L; Baklaushev, Vladimir P; Kovaleva, Oksana A; Chekhonin, Vladimir P; Vassetzky, Yegor S; Avdieiev, Stanislav S; Bakker, Bjorn; Taudt, Aaron S; Belderbos, Mirjam E; Porubsky, David; Spierings, Diana CJ; de Jong, Tristan V; Halsema, Nancy; Kazemier, Hinke G; Hoekstra-Wakker, Karina; Bradley, Allan; de Bont, Eveline SJM; van den Berg, Anke; Guryev, Victor; Lansdorp, Peter M; Tatche, Maria Colome; Foijer, Floris; Liehr, Thomas; Baudoin, Nicolaas C; Nicholson, Joshua M; Soto, Kimberly; Quintanilla, Isabel; Camps, Jordi; Cimini, Daniela; Durrbaum, M; Donnelly, N; Passerini, V; Kruse, C; Habermann, B; Storchova, Z; Mandrioli, Daniele; Belpoggi, Fiorella; Silbergeld, Ellen K; Perry, Melissa J; Skotheim, Rolf I; Lovf, Marthe; Johannessen, Bjarne; Hoff, Andreas M; Zhao, Sen; SveeStromme, Jonas M; Sveen, Anita; Lothe, Ragnhild A; Hehlmann, R; Voskanyan, A; Fabarius, A; Bocking, Alfred; Biesterfeld, Stefan; Berynskyy, Leonid; Borgermann, Christof; Engers, Rainer; Dietz, Josef; Fritz, A; Sehgal, N; Vecerova, J; Stojkovicz, B; Ding, H; Page, N; Tye, C; Bhattacharya, S; Xu, J

Telemedizin, datenbasierte Gesundheitsanalysen, Health-Apps und mobile Geräte zur individuellen Gesundheitskontrolle – immer mehr Gesundheitsdienstleistungen werden mit Hilfe digitaler Dienste und Strukturen angeboten. Vor diesem Hintergrund beleuchten Daten- und Verbraucherschützer, Mediziner und Gesundheitsapp-Entwickler, Rechts- und Gesellschaftswissenschaftler die fachliche Vielfalt der Thematik – und geben viele konkrete Impulse, wie E-Health-Innovationen gefördert und zugleich die Rechte und Interessen von Patienten gewahrt werden.

Dietary lipids change membrane phenotypes, which can be used to affect lineage specification in stem cells., Mammalian cells produce hundreds of dynamically regulated lipid species that are actively turned over and trafficked to produce functional membranes. These lipid repertoires are susceptible to perturbations from dietary sources, with potentially profound physiological consequences. However, neither the lipid repertoires of various cellular membranes, their modulation by dietary fats, nor their effects on cellular phenotypes have been widely explored. We report that differentiation of human mesenchymal stem cells (MSCs) into osteoblasts or adipocytes results in extensive remodeling of the plasma membrane (PM), producing cell-specific membrane compositions and biophysical properties. The distinct features of osteoblast PMs enabled rational engineering of membrane phenotypes to modulate differentiation in MSCs. Specifically, supplementation with docosahexaenoic acid (DHA), a lipid component characteristic of osteoblast membranes, induced broad lipidomic remodeling in MSCs that reproduced compositional and structural aspects of the osteoblastic PM phenotype. The PM changes induced by DHA supplementation potentiated osteogenic differentiation of MSCs concurrent with enhanced Akt activation at the PM. These observations prompt a model wherein the DHA-induced lipidome leads to more stable membrane microdomains, which serve to increase Akt activity and thereby enhance osteogenic differentiation. More broadly, our investigations suggest a general mechanism by which dietary fats affect cellular physiology through remodeling of membrane lipidomes, biophysical properties, and signaling.

In the case of bone defects, there are two different methods to close such defects. One option is to use bone autografts, but therefore the bone graft has to be cut off from the same person’s hip. In this case the patient has to undergo an additional surgery, which bears complications, like causing inflammations. Absorbable, open-pored implants minimize these risks. Synthetic bone implants are typically made of ceramics, bioglass or polymers. In this study, magnesium alloys were investigated as absorbable porous bone substitute materials in which the bone can grow into. The main advantages are the design flexibility to produce individual implants by investment casting and mechanical properties similar to the bone. In order to adapt the degradation behavior to the bone’s ingrowth behavior, the implant material has to be alloyed and coated. Moreover, to meet the mechanical requirements, finite element simulations of the sponge structure were used during the design phase of the structures and compression tests were conducted for experimental validation.

Within the scope of the Collaborative Research Centre (CRC) 1153 novel process chains for the production of hybrid solid components by Tailored Forming are developed at the Leibniz Universität Hannover. The combination of e. g. aluminium with steel allows to produce hybrid compounds with wear-resistant functional surfaces and reduced weight. In these process chains, joining takes place as the first step to produce hybrid semi-finished products by friction welding, cladding, ultrasonic assisted laser welding or co-extrusion, which are subsequently subjected to various forming processes such as forging or impact extrusion. The coaxially joined hybrid semifinished components investigated in this work were produced by means of the lateral angular co-extrusion (LACE) process using the aluminium alloy EN AW-6082 and the case-hardening steel 20MnCr5. These semi-finished products shall be suited to produce hybrid bearing bushings by die forging in a subsequent process step. Initial investigations for the determination of the process parameters and the appropriate tool geometry were made using a steel rod. In future investigations, a steel tube will replace the steel rod in order to produce hybrid semi-finished products, which can be fully integrated into the process chain. The mechanical properties of the profile were determined at different positions along its length. For this purpose, the quality of the joining zone between aluminium and steel as a function of the profile position was examined by means of push-out tests. Moreover, the mechanical properties of the aluminium component's longitudinal weld seam were determined by micro-tensile-tests. © 2017 Trans Tech Publications, Switzerland.

Neodymium containing magnesium alloys like MgNd2 and ZNdK100 offer high corrosion resistance and biocompatibility due to low amounts of alloying elements, and are thus attractive for biomedical applications. Compared with common bioresorbable magnesium alloys, which frequently contain mischmetal, the use of neodymium as a single rare earth element provides for good reproducibility of the degradation behavior while improving the ductility, leading to high fracture strains of 25–30%. Thus, stents made from these alloys allowed dilatation without failure. The MgNd2 alloy’s strength, however, turned out to be low. Recent investigations proved that the strength of a ZNdK100 alloy can be significantly increased by an adaptation of the extrusion parameters, such as billet temperature and extrusion ratio, which govern recrystallization of the microstructure. In the current study, it is demonstrated how the mechanical properties can be adjusted by the extrusion process, allowing the future use of the same alloy for both bone implants and soft tissue implants.

Magnetic magnesium alloys have inherent magnetic properties due to the alloying element cobalt. Thus, the entire structural component made from such an alloy can be utilized for mechanical load measurements using the harmonic analysis of eddy current signals. Because the solubility of cobalt in the magnesium matrix is negligible, the magnetic properties mainly originate from cobalt-rich precipitates. Both the mechanical properties and the magnetic properties are influenced significantly by other alloying elements, such as zinc, as well as the material’s microstructure. Two issues of the ternary magnetic magnesium alloy Mg-Co4-Zn2 are described in this study. The magnetic properties were characterized by using the magnetoelastic effect and the harmonic analysis of eddy current signals. In addition, the mechanical properties of specimens made from the extruded profiles were determined using tensile and rotating bending tests. A substantial dependence on the processing conditions was observed both for the mechanical and magnetic properties.

The combination of light metals and steels allows for new lightweight components with wear-resistant functional surfaces. Within the Collaborative Research Centre 1153 novel process chains are developed for the manufacture of such hybrid components. Here, the production process of a hybrid bearing bushing made of the aluminium alloy EN AW-6082 and the case-hardened steel 20MnCr5 is developed. Hybrid semi-finished products are an attractive alternative to conventional ones resulting from massive forming processes where the individual components are joined after the forming process. The actual hybrid semi-finished products were manufactured using a lateral angular co-extrusion (LACE) process. The bearing bushings are subsequently produced by die forging. In the present study, a tool concept for the LACE process is described, which renders the continuous joining of a steel rod with an aluminium tube possible. During the LACE process, the rod is fed into the extrusion die at an angle of approx. 90°. Metallogr...

Effect of low-cycle room-temperature reverse bending on the crystallographic texture, metallo-graphic structure, and mechanical properties of sheets of ZE10 magnesium alloy after hot rolling and annealing has been studied. The initial texture is characterized by a wide scatter of basal poles in the transverse direction. In the process of reverse bending, the changes in the initial texture and structure (which is represented by equiaxed grains containing twins) lead to regular changes in the anisotropy of mechanical properties.

Magnetic magnesium alloys have an inherent load-sensitive behavior. These alloys are manufactured by casting of magnesium alloyed with the ferromagnetic element cobalt. In this context, the magnetoelastic effect can be used in order to measure mechanical loads during the component's service by means of a harmonic analysis of eddy current signals. The utilization of magnetic magnesium as a load-sensitive material in order to measure mechanical loads in structural components has been demonstrated in previous works. Another application is the magnetic labeling of the alloy. In this context the magnetic remanence is a significant characteristic value. A data track can be written directly on the material's surface by means of an electromagnetic write head. The track may contain relevant component-specific information like serial numbers, manufacture date and expected lifetime. This information can be read out by means of a sensor utilizing the giant magnetoresistive (GMR) effect. The magnetic labeling in relation to the manufactured alloy and the cooling rate during the casting process is examined in this work. The magnetic labeling of three alloys based on magnesium, cobalt and zinc has been investigated; these are MgCo4 and MgCo4Zn2. The alloys’ mechanical as well as their magnetic properties are significantly influenced by these additional alloying elements. In order to investigate the alloys’ suitability for magnetic data storage the quality of the data tracks read out using a GMR sensor are compared depending on the alloy composition. The magnetic labeling is influenced by the microstructure regarding solidification and cooling rate. A conical casting geometry with different solidification rates in top and bottom sections was used for an examination of the relationship between the density of the magnetic phases and the quality of the magnetic labeling.

Familial hyperlipidemias including but not limited to familial hypercholesterolemia (FH) are often evaluated distinctly from population-based hyperlipidemias. We asked whether this practice is warranted either by greater coronary artery disease (CAD) risk or by different detailed lipid profiles in

Zur Verbesserung der Korrosionsbestandigkeit von Magnesiumlegierungen wird vielfach Aluminium als Legierungselement gewahlt. Neuere Untersuchungen zeigen, dass alternativ durch Zulegieren geringer Anteile von Zink die Korrosionsrate binarer Magnesium-Zink-Legierungen vermindert werden kann. Basierend auf diesen Ergebnissen wurden niedriglegierte MgZn-Legierungen in verschieden konzentrierten chloridhaltigen Medien gravimetrisch und elektrochemisch untersucht. Es konnte festgestellt werden, dass sich geringe Zink-Gehalte positiv auf das Korrosionsverhalten auswirken, sowohl in niedrig- als auch in hochkonzentrierten NaCl-Losungen. Eine Korrelation der Ergebnisse aus gravimetrischen und elektrochemischen Messungen wurde von den Tendenzen her festgestellt und mit mikrocomputertomographischen Analysen belegt.

The magnesium-neodymium alloy MgNd2 offers an elongation of 30%. Therefore, it is well suited as a material for resorbable stents which can be used for treating chronic sinusitis. While the alloy’s corrosion properties were already investigated in vitro, the present study focuses on the in vivo degradation behavior of fluoride-coated and uncoated specimens in direct contact with porcine nasal mucosa during a period of 180 days. The study showed a promising and controlled biodegradation, which was investigated by measurements of the MgNd2 specimens’ mass and volume losses as well as element analyses on the surface to obtain information about the composition of the degradation layer. The degradation rates of the uncoated samples in direct contact with the physiological tissue showed a maximum during the first 45 days which then decreased for the remaining implantation period. In contrast, the degradation rates of the fluoride-coated samples increased gradually during the implantation duration.

The magnetic properties of lightweight alloys based on magnesium and cobalt offer a novel way to measure mechanical loads throughout the entire structural component using the magnetoelastic effect. Since the solubility of cobalt in the magnesium matrix is negligible, the magnetic properties mainly originate from Co-rich precipitates. Size and distribution of the Co-containing phases within the alloy's microstructure can be influenced during the initial processing method of the alloy. Specifically, the cooling rate in the casting processes has a major influence on the resulting magnetic properties. In this study, Mg-Co-based alloys were produced by several casting methods which feature substantially different cooling rates, i.e. gravity sand casting, gravity die casting and high-pressure die casting. The differences between the manufactured alloys’ micro- and phase structures are compared and the superior magnetic and mechanical properties of the high-pressure die cast material are demonstrated.

Magnetic magnesium alloys can be utilized as a load sensitive material, in which the inverse magnetostrictive effect is used in order to measure the actual loads in structural components manufactured from such lightweight sensor alloys. To achieve a material which exhibits magnetic properties, Mg is alloyed with ferromagnetic materials like cobalt or samarium-cobalt. Alloying elements commonly used with Mg are utilized to improve the mechanical properties of these alloys, which however may have a slight negative impact on the magnetic sensitivity. In this work, two separate magnetic Mg alloys are compared, each with properties matched to the opposing requirements: (a) high load sensitivity and (b) satisfactory mechanical properties, respectively. The precipitation behavior of the ferromagnetic constituent Co in Mg together with other alloying elements is shown on the basis of SEM images. In addition, the dissolving behavior of the Co powder during the casting process of a binary Mg–Co alloy is investigated. Cyclic loading tests employing harmonic analyses of eddy current signals are utilized in order to verify the alloys’ sensory properties. The mechanical properties are investigated using tensile tests.

In eukaryotic cells, the trans-Golgi network serves as a sorting station for post-Golgi traffic. In addition to coat- and adaptor-mediated mechanisms, studies in mammalian epithelial cells and yeast have provided evidence for lipid-dependent protein sorting as a major delivery mechanism for cargo sorting to the cell surface. The mechanism for lipid-mediated sorting is the generation of raft platforms of sphingolipids, sterols and specific sets of cargo proteins by phase segregation in the TGN. Here, we review the evidence for such lipid-raft-based sorting at the TGN, as well as their involvement in the formation of TGN-to-PM transport carriers. This article is part of a Special Issue entitled Lipids and Vesicular Transport.

To improve the mechanical properties, the castability as well as the corrosion resistance of magnesium alloys, aluminium is frequently employed. As a rule, technically relevant alloys contain between 3 and 9 wt% aluminium. Normally, aluminium contents under 3 wt% is said to have no corrosion reducing effect. In order to investigate the influence of specific additions of aluminium, various methods are employed in practice and different electrolytes or concentrations of saline solutions are used as testing media. In doing this, it is rarely possible to compare the results. For this reason, the current work both discusses the influence of aluminium and the effect of different saline solutions on the corrosion behaviour of low alloy magnesium–aluminium alloys as well as compares two different measuring procedures (electrochemical and gravimetric).

Biodegradable and biocompatible magnesium alloys appear to be very promising not only for temporary clinical application but also for developing deformable and degradable medical implants. This study analyzes the in vivo degradation behavior and the impact on the paranasal sinuses of the highly ductile Mg-2 wt%Nd alloy (MgNd2) in order to provide a basis for a satisfying stent system for the therapy of a chronic sinusitis. Moreover, in vitro tests were carried out on primary porcine nasal epithelial cells (PNEC). For the in vivo tests, cylindrical MgNd2 specimens were implanted into the sinus' mucosa of minipigs. During and after a total period of 180 days the long-term biodegradation and biocompatibility properties after direct contact with the physiological tissue were analyzed. Biodegradation was investigated by measuring the mass and volume losses of the MgNd2 specimens as well as by performing element analyses to obtain information about the degradation layer. The influence on the surrounding tissue of paranasal sinuses was evaluated by endoscopic and histopathological examinations of the mucosa. Here, only a locally unspecific chronic infection was found. The degradation rate showed a maximum after 45 days postsurgery and was determined to decrease subsequently. In vitro experiments using PNEC showed adequate biocompatibility of MgNd2. This study demonstrates a good in vivo biocompatibility for MgNd2 in the system of paranasal sinuses and underlines the promising properties of alloy MgNd2 for biodegradable nasal stent applications.

Die AOK Nordost möchte eine elektronische Patientenakte anbieten, auf die Leistungserbringer nach Zustimmung des Patienten zugreifen können. Ein Konsortium arbeitet derzeit an der Ausgestaltung der Akte.

In this article, manufacture of a magnetic magnesium alloy based on the known magnesium alloys AZ91 or ZEK200 together with samarium–cobalt is investigated. The objective of the investigations is to produce an Mg alloy by die casting, possessing both magnetic characteristics and satisfactory mechanical properties with the aim of obtaining an Mg alloy which can be utilized as a lightweight sensor material. Inverse magnetostriction (Villari Effect) is exploited in order to verify the instantaneous operating forces in lightweight structural components made from Mg such as a vehicle's stub axle. The magnetic properties subject to cyclic loading are determined with the aid of a harmonic analyze of eddy current signals. Results show that for an MgSmCoZn alloy, an unambiguous linear dependency exists between the applied mechanical loading and the harmonic's measured values. The mechanical properties of the MgSmCoZn cast alloy have a similar order of magnitude as those of Mg alloys employed in engineering, such as for example AZ91, and thus possess a good standard.

With the aid of multiple wire drawing passes, the magnesium alloys ZEK100, MgCa0.8, and AL36 were reduced to monofilament wires possessing diameters between 0.5 and 0.1 mm. These filaments were subsequently twisted into poly-filament suture material using stranding. In order to analyze the microstructural constituents and the mechanical-tribological properties, metallographic specimens were prepared and tensile tests were performed on both monofilament as well as poly-filament wire strands. Appropriate parameters were ascertained for the wire drawing process with regard to forming rate, temperature, and heat treatment. During the investigations, the alloy ZEK100 exhibited particularly interesting mechanical properties which, owing to its high tensile strengths (up to 550 MPa for monofilament) and fracture strains (up to 30% for poly-filament), are comparable to those of conventional polymer-based suture materials. In addition to this, integrating a core (internal, individual wire) into the poly-filament mesh of wire strands represents an interesting alternative for future research in which structures composed of different materials, and the advantages of combining their properties are brought into particular focus.

This paper presents a method for the magnetic data storage on the surface of gentelligent components. One key issue is the possibility to store customers’ data on components dynamically and to read it out later on. The data storage is carried out magnetically and is demonstrated on a high-speed milling head. As such components are mostly made of light materials without magnetic properties; areas for the data storage on the surface must first be defined. Sintered components made of Mg and of hard magnetic particles have the potential to meet these requirements.

Lipidomics is a rapidly growing technology for identification and quantification of a variety of cellular lipid molecules. Following the successful development and application of functional genomic technologies in yeast Saccharomyces cerevisiae, we witness a recent expansion of lipidomics applications in this model organism. The applications include detailed characterization of the yeast lipidome as well as screening for perturbed lipid phenotypes across hundreds of yeast gene deletion mutants. In this chapter, we describe sample handling, mass spectrometry, and bioinformatics methods developed for yeast lipidomics studies.